Restoration of Auditory and Vestibular Functions in Adult Mouse Model of Deafness DFNA41 by Single-Dose Genome Editing Therapy

Genome editing has shown the potential to treat genetic hearing loss. However, current editing therapies for genetic hearing loss have shown effect in the rescue of hearing loss only. In this study, we evaluated a rescue strategy by AAV2-mediated delivery of SaCas9/sgRNA in the mature inner ear of P2rx2V61L/+ mouse model of DFNA41, dominant delayed onset and progressive hearing loss in humans. We demonstrate that adult local injection results in efficient and specific editing that abolishes the mutation without significant off-target effect or AAV genome integration. Editing effectively restores long-term auditory and vestibular function. Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss (NIHL), a feature identified in DFNA41 patients. Intervention at a juvenile stage broadens the frequency range rescued, highlighting the importance of early intervention. An effective gRNA for the human P2RX2 V60L mutation has been identified. Our study establishes the feasibility of editing to treat DFNA41 due to P2RX2 V60L mutation in humans and opens an avenue of using editing to rescue hearing and vestibular function while mitigating noise-induced hearing loss.